在p53丧失后癌症基因组的有序和决定性演变
Timour Baslan1, John P Morris1,2,3, Zhen Zhao1,4
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|August 17, 2022
概括
对于基因组稳定至关重要的瘤抑制剂p53的丧失在胰腺癌发育过程中具有可预测的进化路径. 这一发现为TP53突变癌症提供了新的治疗点.
科学领域:
- 癌症学
- 遗传学
- 基因组学
背景情况:
- 在人类癌症中,p53失活是常见的现象,促进基因组不稳定.
- 在瘤形成中p53损失后的精确基因组进化模式尚不清楚.
研究的目的:
- 在胰腺管腺癌中对p53无活化后的基因组进化模式进行研究.
- 确定p53损失是否导致癌症发展过程中可预测或混乱的基因组变化.
主要方法:
- 使用胰腺管腺癌的小鼠模型,早期失去了p53的异性.
- 使用单细胞测序和现场基因定型来追踪从p53无活化到癌症的基因组演变.
- 在恶性前和恶性进展过程中分析了组织学阶段以及基因组变化.
主要成果:
- 胰腺癌进展中的p53无活化遵循一个决定性的四个阶段的基因组进化:异构性丧失,缺失,基因组倍增和增益/放大.
- 删除事件针对特定的途径并成为固定的,尽管整体的基因组异质性.
- 基因组进化的每个阶段都与不同的组织学阶段相关.
结论:
- 不仅仅是导致遗传混乱的门户,而且还可以驱动可预测的基因组进化模式.
- 了解这些决定性模式可能会揭示TP53突变癌症的新疗法.
相关概念视频
Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
DNA Damage can Stall the Cell Cycle
9.3K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.3K
Cancer-Critical Genes II: Tumor Suppressor Genes
7.9K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
7.9K
Loss of Tumor Suppressor Gene Functions
5.1K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
5.1K
Cancers Originate from Somatic Mutations in a Single Cell
12.5K
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
12.5K
Adaptive Mechanisms in Cancer Cells
5.9K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.9K


